Petros Grivas, MD, PhD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, clinical director, Genitourinary Cancers Program, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses several unmet needs within urothelial cancer, as well as how to potentially ameliorate them.

When attempting to improve quality of life for patients with urothelial cancer, it is important to employ strategies that account for both disease and treatment burden, Grivas begins. Accordingly, efforts should not just be focused on improving disease control, but rather also include obtaining and measuring patient-reported outcomes to better assess the patient's experience 

Similarly, efforts to identify and address disparities in cancer care are critical to improve patient outcomes and increase equality, diversity, and inclusion in care across tumor types, Grivas explains. Strategies should aim to reduce barriers to treatment, improve the inclusion of minorities and other underrepresented groups in clinical trials, and facilitate social and familial support, Grivas states. Healthcare providers should also promote resources or programs that help patients and their families cope with 

The frequency of germline mutations in urothelial cancer, particularly in bladder or upper urinary tract cancers, has greatly increased in the last decade, Grivas continues, adding that the detection of germline mutations is therefore critical to informing treatment decisions in urothelial cancer. Moreover, it is important to ensure that a patient's family history has been obtained, and that they undergo germline testing. In turn, this may also educate families about their hereditary risk for developing urothelial cancer and direct them towards early cascade testing and other cancer prevention strategies, he notes.

Lastly, ongoing efforts to develop and validate biomarkers in urothelial cancer increasingly require tools like germline testing to identify patients who may benefit from targeted therapies, Grivas states. As these biomarker-driven therapies continue to expand and improve in efficacy, germline testing will become even more integral to patient selection, he concludes.

Videos

Petros Grivas, MD, PhD, discusses several unmet needs within urothelial cancer, as well as how to potentially ameliorate them.
 

Dr Grivas on Addressing Unmet Needs in Urothelial Cancer

Petros Grivas, MD, PhD, professor, Clinical Research Division, Fred Hutch Cancer Center, clinical director, Genitourinary Cancers Program, University of Washington Medicine, professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, discusses findings from the primary analysis of cohort 3 of the phase 2 TROPHY U-01 trial (NCT03547973) in patients with metastatic urothelial cancer.

Cohort 3 of TROPHY U-01 consisted of adult patients with metastatic urothelial cancer who had progressed following treatment with platinum-based chemotherapy in the metastatic setting or within 12 months of completing platinum-based chemotherapy in the neoadjuvant or adjuvant setting and were naïve to checkpoint inhibitors. Patients in this single-arm cohort received sacituzumab govitecan-hziy (Trodelvy) at 10 mg/kg on days 1 and 8 plus pembrolizumab (Keytruda) at 200 mg on day 1 of each 21-day cycle. The primary end point of this cohort was overall response rate (ORR), with a target ORR of 41%.

In cohort 3, the ORR with sacituzumab govitecan and pembrolizumab was 41%, meeting the cohort’s primary end point, Grivas says. Of the responders, 8 achieved a complete response (CR), translating to a 20% CR rate, and the clinical benefit rate was 46%. Responses were seen across prespecified patient subsets, including those with liver metastases, those with visceral metastases, and those with 2 Bellmunt risk factors, Grivas explains. In addition, 72% of the evaluable patients experienced tumor reduction.

The median duration of response was 11.1 months, which further supports the hypothesis that adding pembrolizumab to sacituzumab govitecan results in deep and durable responses, Grivas emphasizes. The median progression-free survival (PFS) in cohort 3 was 5.32 months and the median overall survival (OS) was 12.75 months. Although TROPHY U-01 is a single-arm phase 2 trial with patient selection bias that warrants caution when considering these PFS and OS data, these efficacy signals are promising, Grivas concludes.

Petros Grivas, MD, PhD, discusses findings from the primary analysis of cohort 3 of the phase 2 TROPHY U-01 trial in patients with metastatic urothelial cancer.

Dr Grivas on Sacituzumab Govitecan Plus Pembrolizumab in Metastatic Urothelial Cancer

Petros Grivas, MD, PhD, physician, Fred Hutchinson Cancer Center, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, clinical director, Genitourinary Cancers Program, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses key baseline characteristics from the real-world PATRIOT II study of first-line avelumab (Bavencio) maintenance therapy in metastatic urothelial cancer (mUC). 

The ongoing, retrospective study of maintenance avelumab stemmed from results of the phase 3 JAVELIN Bladder 100 trial (NCT02603432), which showed that avelumab maintenance plus best supportive care elicited significant overall survival and progression-free survival benefits vs best supportive care alone in patients with locally advanced or metastatic urothelial cancer who did not progress on first-line platinum-based chemotherapy.

To investigate real-world treatment patterns and patient characteristics for those receiving avelumab maintenance, PATRIOT-II collected data from 37 geographically dispersed oncology practices/communities and academic centers in the United States, Grivas begins. The study retrospectively enrolled select patients who went on to receive avelumab maintenance, and those who progressed during first-line chemotherapy were excluded from the study. Of the 160 patients included in the study thus far, 31% had upper tract disease, 49% had lower tract disease, 3% had upper and lower tract disease, and 18% had an unknown site of primary tumor.

The median duration of chemotherapy administration was 13 weeks, and the median number of chemotherapy cycles was 5. Thirteen percent of patients experienced a complete response to chemotherapy, and 68% had a partial response. The remaining patients exhibited stable disease (11%) or had unknown response status (8%). The median time to first imaging after chemotherapy initiation was 10 weeks, which was consistent with clinical practice, Grivas says. Moreover, 14% were hospitalized while receiving chemotherapy, and 16% went to the emergency department.

These baseline characteristics were generally consistent with therapy paradigms in the frontline induction setting, as a similar proportion of patients in the general population would have medical comorbidities, Grivas explains. Patients proceeded to first-line avelumab maintenance at a median of 4 weeks following the completion of chemotherapy, which was a shorter duration compared with patients from JAVELIN Bladder 100, Grivas concludes.

Future analyses from PATRIOT II will further examine treatment patters and clinical outcomes for avelumab maintenance.

Dr Grivas reports serving as a consultant or in an advisory role for

4D Pharma, Aadi Bioscience, Asieris, Astellas Pharma, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, G1 Therapeutics, Genentech, Gilead Sciences, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence, Mirati Therapeutics, MSD, Pfizer, PureTech, Regeneron, Roche, Seattle Genetics, Silverback Therapeutics, Strata Oncology, QED Therapeutics, Merck KGaA, and UroGen Pharma; he reports institutional research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm Group, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Mirati Therapeutics, MSD, Pfizer, QED Therapeutics, and Merck KGaA.

Petros Grivas, MD, PhD, discusses key baseline characteristics from the real-world PATRIOT II study of first-line avelumab maintenance therapy in metastatic urothelial cancer. 

Dr. Grivas on the Real-World Study of Avelumab Maintenance in Metastatic Urothelial Carcinoma

Petros Grivas, MD, PhD, physician, Fred Hutchinson Cancer Center, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, clinical director, Genitourinary Cancers Program, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center, discusses the investigation of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) in metastatic urothelial carcinoma.

Historically, achieving cures for patients with metastatic urothelial carcinoma has been a challenge, specifically among patients who are platinum refractory, since they have a poor prognosis, Grivas says. Novel agents, such as the antibody-drug conjugate enfortumab vedotin, have demonstrated activity as a single agent in metastatic urothelial carcinoma; however, in later settings, response rates tend to fall.

Investigators hope to continue to expand the treatment armamentarium for metastatic urothelial carcinoma with the addition of subsequent therapies. As these therapies emerge, learning how to sequence them and use them in potential combinations could produce more benefit, Grivas says. 

One example of a novel combination is enfortumab vedotin and pembrolizumab. The phase 1/2 EV-103 trial (NCT03288545) examined this combination and enfortumab vedotin alone in patients with locally advanced or metastatic urothelial cancer, eliciting efficacy and tolerability, Grivas explains. 

Data from cohort K of the trial presented at the 2022 ESMO Congress

 showed that among 76 patients treated with the combination, the overall response rate (ORR) was 64.5% with a median duration of response (DOR) that was not reached. In 73 patients treated with enfortumab vedotin alone, the ORR was 45.2% with a median DOR of 13.2 months.

 to a supplemental biologics license applications for enfortumab vedotin and pembrolizumab used in combination for the treatment of patients with locally advanced or metastatic urothelial cancer who are not eligible to receive cisplatin-containing chemotherapy. The combination is under further evaluation in the ongoing phase 3 KEYNOTE-A39/EV-302 trial (NCT04223856) in patients with previously untreated advanced urothelial carcinoma. 

Petros Grivas, MD, PhD, discusses the investigation of enfortumab vedotin and pembrolizumab in metastatic urothelial carcinoma.

Dr. Grivas on Enfortumab Vedotin Plus Pembrolizumab in Metastatic Urothelial Carcinoma

Petros Grivas, MD, PhD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, clinical director, Genitourinary Cancers Program, UW Medicine, associate professor, Clinical Research Division, Fred Hutchinson Cancer ResearchCenter, discusses the future of the phase 2 TROPHY U-01 trial (NCT03547973) regimen in metastatic urothelial cancer.

Cohort 3 of the TROPHY-U-01 trial evaluated sacituzumab govitecan-hziy (Trodelvy) in combination with pembrolizumab (Keytruda) in patients with metastatic urothelial cancer who have progressed following a platinum-based chemotherapy in the front-line setting.

The objective response rates seen were promising when considering the number of patients who presented with multiple negative prognostic and risk factors, Grivas says. Moreover, response rates seen with prior chemotherapy were low, and many patients experienced rapid disease progression, Grivas adds. Taking these baseline characteristics into consideration, the 34% response rate and 63% of reduction in tumor size seen in patients was considerable, Grivas says.

Overall, this combination is active and merits further investigation in the platinum-refractory and first-line settings, Grivas continues. Although the data are not practice changing yet, the findings support further investigation of this combination in different lines of therapy, Grivas concludes.

Petros Grivas, MD, PhD, discusses the future of the phase 2 TROPHY U-01 trial regimen in metastatic urothelial cancer.


Dr. Grivas on the Future of the TROPHY U-01 Regimen in Urothelial Cancer

Petros Grivas, MD, PhD, physician, Fred Hutchinson Cancer Center, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, clinical director, Genitourinary Cancers Program, UW Medicine, associate member, Clinical Research Division, Fred Hutchinson Cancer Center, discusses the phase 2 TROPHY U-01 trial (NCT03547973) in metastatic urothelial cancer.

Cohort 3 of TROPHY-U-01 evaluated sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda) in patients with metastatic urothelial cancer who progressed after platinum-based chemotherapy in the frontline setting.

Notably, this cohort included patients who received neoadjuvant or adjuvant chemotherapy if they recurred within 12 months from their last dose of chemotherapy, Grivas explains.

Patients were not eligible if they had an active autoimmune disease, and they must have recovered from prior treatment-related toxicities, Grivas continues. The eligibility criteria aimed to mirror what is typically seen with urothelial cancer in clinical practice, Grivas concludes.

Petros Grivas, MD, PhD, discusses the phase 2 TROPHY U-01 trial in metastatic urothelial cancer.


Dr. Grivas on the TROPHY U-01 Trial in Urothelial Cancer

Petros Grivas, MD, PhD, physician, Seattle Cancer Care Alliance, associate professor, Division of Medical Oncology, University of Washington (UW) School of Medicine, clinical director, Genitourinary Cancers Program, UW Medicine, associate member, Clinical Research Division, Fred Hutchinson Cancer Center, discusses the utility of enfortumab vedotin-ejfv (Padcev) in the second- and third-line setting for patients with urothelial carcinoma.

Enfortumab vedotin is indicated for use in the second-line setting for patients who are not eligible for cisplatin, and for those who received first-line treatment with chemotherapy or a checkpoint inhibitor, according to Grivas. This is based on data from cohort 2 of the phase 2 EV-201 trial (NCT03219333), in which the agent demonstrated a response rate of 52% in 89 patients with this disease, Grivas says. 

In the third-line setting, results from the phase 3 EV-301 trial (NCT03474107) demonstrated that the agent had level 1 evidence of significant overall survival and progression-free survival benefit. The agent also produced higher response rates vs chemotherapy in this population, Grivas explains. This evidence confirms the utility of enfortumab vedotin in the third-line setting for patients who were previously treated with chemotherapy and immunotherapy, Grivas concludes. 

Petros Grivas, MD, PhD, discusses the utility of enfortumab vedotin-ejfv in the second- and third-line setting for patients with urothelial carcinoma.

Dr. Grivas on Enfortumab Vedotin in Second- and Third-Line Urothelial Carcinoma 

Petros Grivas, MD, PhD, physician of the Seattle Cancer Care Alliance; associate professor in the Department of Medicine in the Division of Oncology and clinical director of the Genitourinary Cancers Program at the University of Washington School of Medicine; and associate member of the Clinical Research Division at Fred Hutchinson Cancer Center, discusses findings from the subgroup analyses of JAVELIN Bladder 100 in advanced urothelial cancer.

​The phase 3 JAVELIN Bladder 100 trial ​randomized patients with unresectable locally advanced or metastatic urothelial carcinoma to frontline avelumab (Bavencio) maintenance plus best supportive care (BSC) versus BSC alone.

Avelumab plus BSC demonstrated statistically significant overall survival and progression-free survival benefits compared with BSC alone across all prespecified subgroups, ​Grivas says.

Moreover, the benefits were observed regardless of patients’ best response to induction chemotherapy and ​site of metastasis at baseline.

As such, all patients with ​advanced urothelial carcinoma who derive a response or stable disease ​from induction chemotherapy should receive avelumab maintenance, Grivas concludes.

Petros Grivas, MD, PhD, discusses findings from the subgroup analyses of JAVELIN Bladder 100 in advanced urothelial cancer.

Dr. Grivas on the Subgroup Analyses of the JAVELIN Bladder 100 Trial in Advanced Urothelial Cancer

Petros Grivas, MD, medical oncologist, Seattle Cancer Care Alliance, associate professor, University of Washington and Fred Hutchinson Cancer Center, discusses comparisons between 

 mutations in metastatic castration-resistant prostate cancer (mCRPC).

 genes have been identified in patients with prostate cancer. When looking at the totality of patients with mCRPC, approximately 12% have germline mutations and 25% of all patients with prostate cancer have somatic mutations, said Grivas.

In the PROfound trial, there was significant activity of olaparib (Lynparza) in selected patients with 

 mutations; the majority of benefit was in patients with BRCA2 mutations. However, there were questions about the benefit in patients with 

 mutations. In this study, it was shown that the response to standard therapies appears compatible with patients who have germline 

 mutations compared with those who do not have germline mutations. The germline 

 mutations did not appear to impact a response to standard therapies in a metastatic castration-resistant setting, concludes Grivas.

Petros Grivas, MD, discusses comparisons between ATM and BRCA1/2 mutations in metastatic castration-resistant prostate cancer.

Dr. Grivas on Comparisons Between ATM and BRCA1/2 Mutations in mCRPC

Petros Grivas, MD, medical oncologist, Seattle Cancer Care Alliance, associate professor, University of Washington and Fred Hutchinson Cancer Center, discusses searching for biomarkers in patients with urothelial cancer to indicate response to pembrolizumab (Keytruda) in the KEYNOTE-052 trial.

In this phase II trial, Grivas and his team found that patients with a low Stromal/EMT/TGF-β signature expression in the tumor microenvironment had better signaling and a better response to pembrolizumab.

Likewise, patients with high Stromal/EMT/TGF-β signature expression was associated with resistance to pembrolizumab independently of gene expression profile or PD-L1 expression in patients with urothelial carcinoma.

Petros Grivas, MD, discusses searching for biomarkers in patients with urothelial cancer to indicate response to pembrolizumab in the KEYNOTE-052 trial.

Petros Grivas, MD

Articles